Branched alkyl pyrrolidine-3-carboxylic acids

ABSTRACT

Branched alkyl pyrrolidines of formula (I) are disclosed and are useful as agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropatnological disorders. Processes for the preparation and intermediates useful in the preparation are also disclosed.

This appln. is a 371 of PCT/US99/18258 Aug. 11, 1999 which claimsbenefit of 60/100,156 Sep. 14, 1998.

BACKGROUND OF THE INVENTION

Compounds of formula

wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or 6 areknown in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

SUMMARY OF THE INVENTION

The compounds, prodrugs, and pharmaceutically acceptable salts areuseful in a variety of disorders. The disorders include: convulsionssuch as in epilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, depression, anxiety, panic, pain,inflammatory disorders such as arthritis, irritable bowel syndrome, andneuropathological disorders.

The compounds are those of formula

or a pharmaceutically acceptable salt thereof or a prodrug thereofwherein

R₁ is hydrogen or a straight or branched alkyl of from 1 to 5 carbons;

R₂ is a straight or branched alkyl of from 1 to 5 carbons; and

R₁ and R₂ when taken together form a carbocyclic ring of from 3 to 7atoms.

Preferred compounds are those wherein

R₁ is H, methyl, or ethyl; and

R₂ is methyl or ethyl.

The most preferred compounds are those wherein(cis)-4-isobutyl-pyrrolidine-3-carboxylic acid and(trans)-4-isobutyl-pyrrolidine-3-carboxylic acid.

Other preferred compounds are those wherein R₁ and R₂ are taken to forma carbocylic ring of from 3 to 7 atoms.

More preferred compounds are those wherein R₁ and R₂ form a five or sixmembered ring.

Novel intermediates useful in the preparation of the final compounds arealso encompassed by the invention.

Other compounds of the invention are those of Formula IA

or a pharmaceutically acceptable salt thereof wherein R₄ is alkyl of 3or 4 carbons. Such compounds are selected from:

trans-4-isopropylpyrrolidine-3-carboxylic acid;

trans-4-propyl-pyrrolidine-3-carboxylic acid; and

trans-4-butyl-pyrrolidine-3-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention and their pharmaceuticallyacceptable salts and prodrugs are as defined by Formula I above.

The term “alkyl” is a straight or branched group of from 1 to 5 carbonatoms including but not limited to methyl, ethyl, propyl, n-propyl,isopropyl, butyl, 2-butyl, tert-butyl, and pentyl.

Preferred groups are methyl and tert-butyl.

The stereocenters in Formula I can have independently be of either an Ror S configuration.

Compounds of Formula I wherein the two substituents have a cis relativeorientation about the pyrrolidine ring can be prepared in the followingmanner outlined in Scheme 1.

Compounds of Formula I wherein the two substituents have a transrelative orientation about the pyrrolidine ring, can be prepared in thefollowing manner outlined in Scheme 2.

Scheme 5

Compound R₁ R₂ 2 (%) 3 (%) a CH₃ H 100 90 b CH₃ CH₃ 28 84 c C₂H₅ H 95 78d i-Pr H 79 88 e n-Pr H 72 88 f i-Bu H 99 86 g H i-Bu 41 85 h n-Bu H 8285

TABLE I [3H]GAP NA Release CITH DBA 2 Vogel Binding % Inhibition Sys L %MPE % Protect % of Structure IC₅₀ (μM) @ 100 μM IC₅₀ (μM) 1 h 2 h (time)C1-1008

0.140  25 48.9 19.9 100 63.7

0.087 193 52.5 50.1 100 100 100

0.120 >10,000 53 4.6 20 20

0.051 3 −15 0 0

0.700 23 3.3 0 0

0.015 16 20 40 0.63

1.166 8 −0.63

3.101

1.192

0.543

0.030

0.064

Since amino acids are amphoteric, pharmacologically compatible saltswhen R is hydrogen can be salts of appropriate inorganic or organicacids, for example, hydrochloric, sulphuric, phosphoric, acetic, oxalic,lactic, citric, malic, salicylic, malonic, maleic, succinic, andascorbic. Starting from corresponding hydroxides or carbonates, saltswith alkali metals or alkaline earth metals, for example, sodium,potassium, magnesium, or calcium are formed. Salts with quaternaryammonium ions can also be prepared with, for example, thetetramethyl-ammonium ion.

Prodrugs of compounds I-VIII are included in the scope of the instantinvention. Aminoacyl-glycolic and -lactic esters are known as prodrugsof amino acids (Wermuth C. G., Chemistry and Industry, 1980:433-435).The carbonyl group of the amino acids can be esterified by known means.Prodrugs and soft drugs are known in the art (Palomino E., Drugs of theFuture, 1990;15(4):361-368). The last two citations are herebyincorporated by reference.

The effectiveness of an orally administered drug is dependent upon thedrug's efficient transport across the mucosal epithelium and itsstability in entero-hepatic circulation. Drugs that are effective afterparenteral administration but less effective orally, or whose plasmahalf-life is considered too short, may be chemically modified into aprodrug form.

A prodrug is a drug which has been chemically modified and may bebiologically inactive at its site of action, but which may be degradedor modified by one or more enzymatic or other in vivo processes to theparent bioactive form.

This chemically modified drug, or prodrug, should have a differentpharmacokinetic profile to the parent, enabling easier absorption acrossthe mucosal epithelium, better salt formulation and/or solubility,improved systemic stability (for an increase in plasma half-life, forexample). These chemical modifications may be

1) ester or amide derivatives which may be cleaved by, for example,esterases or lipases. For ester derivatives, the ester is derived fromthe carboxylic acid moiety of the drug molecule by known means. Foramide derivatives, the amide may be derived from the carboxylic acidmoiety or the amine moiety of the drug molecule by known means.

2) peptides which may be recognized by specific or nonspecificproteinases. A peptide may be coupled to the drug molecule via amidebond formation with the amine or carboxylic acid moiety of the drugmolecule by known means.

3) derivatives that accumulate at a site of action through membraneselection of a prodrug form or modified prodrug form,

4) any combination of 1 to 3.

Current research in animal experiments has shown that the oralabsorption of certain drugs may be increased by the preparation of“soft” quaternary salts. The quaternary salt is termed a “soft”quaternary salt since, unlike normal quaternary salts, e.g., R—N⁺(CH₃)₃,it can release the active drug on hydrolysis.

“Soft” quaternary salts have useful physical properties compared withthe basic drug or its salts. Water solubility may be increased comparedwith other salts, such as the hydrochloride, but more important theremay be an increased absorption of the drug from the intestine. Increasedabsorption is probably due to the fact that the “soft” quaternary salthas surfactant properties and is capable of forming micelles andunionized ion pairs with bile acids, etc., which are able to penetratethe intestinal epithelium more effectively. The prodrug, afterabsorption, is rapidly hydrolyzed with release of the active parentdrug.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof. For example,the compound of Example 1 is a mixture of all four possiblestereoisomers. The compound of Example 6 is one of the isomers. Theconfiguration of the cyclohexane ring carbon centers may be R or S inthese compounds where a configuration can be defined.

The radioligand binding assay using [³H]gabapentin and the α₂δ subunitderived from porcine brain tissue was used (Gee N. S., Brown J. P.,Dissanayake V. U. K., Offord J., Thurlow R., Woodruff G. N., “The NovelAnti-convulsant Drug, Gabapentin, Binds to the α₂δ Subunit of a CalciumChannel,” J. Biol. Chem., 1996;271:5879-5776).

Compounds can also be assayed for biological activity using a[3H]gabapentin binding assay as described in Suman Chauhan N., et al.,Eur. J. Pharmacol., 1993;244:293-301.

TABLE 2 IC₅₀ (μM) at α₂δ Compound Structure Binding Site Example 1

0.135 Example 2

0.044

Table 2 above shows the binding affinity of the compounds of theinvention to the α₂δ subunit.

The compounds of the invention are compared to Neurontin®, a marketeddrug effective in the treatment of such disorders as epilepsy.Neurontin® is 1-(aminomethyl)-cyclohexaneacetic acid of structuralformula

Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in this assay. Thecompounds of the instant invention are expected, therefore, to exhibitpharmacologic properties comparable to gabapentin. For example, asagents for convulsions, anxiety, and pain.

The present invention also relates to therapeutic use of the compoundsof the mimetic as agents for neurodegenerative disorders.

Such neurodegenerative disorders are, for example, Alzheimer's disease,Huntington's disease, Parkinson's disease, and Amyotrophic LateralSclerosis.

The present invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia.

Stroke refers to a cerebral vascular disease and may also be referred toas a cerebral vascular incident (CVA) and includes acute thromboembolicstroke. Stroke includes both focal and global ischemia. Also, includedare transient cerebral ischemic attacks and other cerebral vascularproblems accompanied by cerebral ischemia. A patient undergoing carotidendarterectomy specifically or other cerebrovascular or vascularsurgical procedures in general, or diagnostic vascular proceduresincluding cerebral angiography and the like.

Other incidents are head trauma, spinal cord trauma, or injury fromgeneral anoxia, hypoxia, hypoglycemia, hypotension as well as similarinjuries seen during procedures from embole, hyperfusion, and hypoxia.

The instant invention would be useful in a range of incidents, forexample, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

Pain refers to acute as well as chronic pain.

Acute pain is usually short-lived and is associated with hyperactivityof the sympathetic nervous system. Examples are postoperative pain andallodynia.

Chronic pain is usually defined as pain persisting from 3 to 6 monthsand includes somatogenic pains and psychogenic pains. Other pain isnociceptive.

Still other pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, causalgia, plexusavulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain isalso caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

Psychogenic pain is that which occurs without an organic origin such aslow back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, bum, and otherforms of neuralgia, neuropathic and idiopathic pain syndrome.

A skilled physician will be able to determine the appropriate situationin which subjects are susceptible to or at risk of, for example, strokeas well as suffering from stroke for administration by methods of thepresent invention.

The compounds of the invention are also expected to be useful in thetreatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

GABA is an inhibitory neurotransmitter with the central nervous system.Within the general context of inhibition, it seems likely thatGABA-mimetics might decrease or inhibit cerebral function and mighttherefore slow function and decrease mood leading to depression.

The compounds of the instant invention may produce an anticonvulsanteffect through the increase of newly created GABA at the synapticjunction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

The compounds of the instant invention are also expected to be useful inthe treatment of anxiety and of panic as demonstrated by means ofstandard pharmacological procedures.

MATERIAL AND METHODS

Carrageenin-Induced Hyperalgesia

Nociceptive pressure thresholds were measured in the rat paw pressuretest using an analgesymeter (Randall-Selitto method: Randall L. O. andSelitto J. J., “A method for measurement of analgesic activity oninflamed tissue,” Arch. Int. Pharmacodyn., 1957;4:409-419). MaleSprague-Dawley rats (70-90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3-300 mg, s.c.), morphine (3 mg/kg, s.c.) orsaline at 3.5 hours after carageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours postcarrageenin.

(R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride was tested inthe above carrageenan-induced hyperalgesia model. The compound was dosedorally at 30 mg/kg, and 1 hour postdose gave a percent of maximumpossible effect (MPE) of 53%. At 2 hours postdose, it gave only 4.6% ofMPE.

Compounds can be tested for antihyperalgesic activity using the methoddescribed in Bennett G. J., et al., Pain, 1988;33:87-107.

Mouse Light/Dark Box

The apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cmhigh, divided into a small (2/5) and a large (3/5) area by a partitionthat extended 20 cm above the walls (Costall B., et al., “Exploration ofmice in a black and white box: validation as a model of anxiety,”Pharmacol. Biochem. Behav., 1989;32:777-785).

There is a 7.5×7.5 cm opening in the center of the partition at floorlevel. The small compartment is painted black and the large compartmentwhite. The white compartment is illuminated by a 60-W tungsten bulb. Thelaboratory is illuminated by red light. Each mouse is tested by placingit in the center of the white area and allowing it to explore the novelenvironment for 5 minutes. The time spent in the illuminated side ismeasured (Kilfoil T., et al., “Effects of anxiolytic and anxiogenicdrugs on exploratory activity in a simple model of anxiety in mice,”Neuropharmacol, 1989;28:901-905).

Rat Elevated X-Maze

A standard elevated X-maze (Handley S.L., et al., “Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior,” Naunyn-Schiedeberg's Arch. Pharmacol.,1984;327:1-5), was automated as previously described (Field, et al.,“Automation of the rat elevated X-maze test of anxiety,” Br. J.Pharmacol., 1991;102(Suppl.):304P). The animals are placed on the centerof the X-maze facing one of the open arms. For determining anxiolyticeffects the entries and time spent on the end half sections of the openarms is measured during the 5-minute test period (Costall, et al., “Useof the elevated plus maze to assess anxiolytic potential in the rat,”Br. J. Pharmacol., 1989;96(Suppl.):312p).

Marmoset Human Threat Test

The total number of body postures exhibited by the animal towards thethreat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

Rat Conflict Test

Rats are trained to press levers for food reward in operant chambers.The schedule consists of alternations of four 4-minute unpunishedperiods on variable interval of 30 seconds signaled by chamber lights onand three 3-minute punished periods on fixed ratio 5 (by footshockconcomitant to food delivery) signaled by chamber lights off. The degreeof footshock is adjusted for each rat to obtain approximately 80% to 90%suppression of responding in comparison with unpunished responding. Ratsreceive saline vehicle on training days.

DBA2 Mouse Model of Anticonvulsant Efficacy

All procedures were carried out in compliance with the NIH Guide for theCare and Use of Laboratory Animals under a protocol approved by theParke-Davis Animal Use Committee. Male DBA/2 mice, 3 to 4 weeks old wereobtained from Jackson Laboratories Bar Harbour, Me. Immediately beforeanticonvulsant testing, mice were placed upon a wire mesh, 4 inchessquare, suspended from a steel rod. The square was slowly invertedthrough 180° and mice observed for 30 seconds. Any mouse falling fromthe wire mesh was scored as ataxic (Coughenour L. L., McLean J. R.,Parker R. B., “A new device for the rapid measurement of impaired motorfunction in mice,” Pharm. Biochem. Behav., 1977;6(3):351-3). Mice wereplaced into an enclosed acrylic plastic chamber (21 cm height,approximately 30 cm diameter) with a high-frequency speaker (4 cmdiameter) in the center of the top lid. An audio signal generator(Protek model B-810) was used to produce a continuous sinusoidal tonethat was swept linearly in frequency between 8 kHz and 16 kHz once each10 msec. The average sound pressure level (SPL) during stimulation wasapproximately 100 dB at the floor of the chamber. Mice were placedwithin the chamber and allowed to acclimatize for one minute. DBA/2 micein the vehicle-treated group responded to the sound stimulus (applieduntil tonic extension occurred, or for a maximum of 60 sec) with acharacteristic seizure sequence consisting of wild running followed byclonic seizures, and later by tonic extension, and finally byrespiratory arrest and death in 80% or more of the mice. Invehicle-treated mice, the entire sequence of seizures to respiratoryarrest lasts approximately 15 to 20 seconds. The incidence of all theseizure phases in the drug-treated and vehicle-treated mice wasrecorded, and the occurrence of tonic seizures were used for calculatinganticonvulsant ED₅₀ values by probit analysis (Litchfield J. T.,Wilcoxon F. “A simplified method for evaluating dose-effectexperiments,” J. Pharmacol., 1949;96:99-113). Mice were used only oncefor testing at each dose point. Groups of DBA/2 mice (n=5-10 per dose)were tested for sound-induced seizure responses 2 hours (previouslydetermined time of peak effect) after given drug orally. All drugs inthe present study were dissolved in distilled water and given by oralgavage in a volume of 10 mL/kg of body weight. Compounds that areinsoluble will be suspended in 1% carboxymethocellulose. Doses areexpressed as weight of the active drug moiety.

The compounds of the instant invention are also expected to be useful inthe treatment of pain and phobic disorders (Am. J. Pain Manag.,1995;5:7-9).

The compounds of the instant invention are also expected to be useful intreating the symptoms of manic, acute or chronic, single upside, orrecurring depression. They are also expected to be useful in treatingand/or preventing bipolar disorder (U.S. Pat. No. 5,510,381).

Models of Irritable Bowel Syndrome

TNBS-Induced Chronic Visceral Allodynia In Rats

Injections of trinitrobenzene sulfonic (TNBS) into the colon have beenfound to induce chronic colitis. In human, digestive disorders are oftenassociated with visceral pain. In these pathologies, the visceral painthreshold is decreased indicating a visceral hypersensitivity.Consequently, this study was designed to evaluate the effect ofinjection of TNBS into the colon on visceral pain threshold in aexperimental model of colonic distension.

MATERIALS AND METHODS

Animals and Surgery

Male Sprague-Dawley rats (Janvier, Le Genest-St-Ilse, France) weighing340-400 g are used. The animals are housed 3 per cage in a regulatedenvironment (20±1° C., 50±5% humidity, with light 8:00 am to 8:00 pm).Under anesthesia (ketamine 80 mg/kg i.p; acepromazin 12 mg/kg ip), theinjection of TNBS (50 mg/kg) or saline (1.5 mL/kg) is performed into theproximal colon (1 cm from the cecum). After the surgery, animals areindividually housed in polypropylene cages and kept in a regulatedenvironment (20±1° C., 50±5% humidity, with light 8:00 am to 8:00 pm)during 7 days.

Experimental Procedure

At Day 7 after TNBS administration, a balloon (5-6 cm length) isinserted by anus and kept in position (tip of balloon 5 cm from theanus) by taping the catheter to the base of the tail. The balloon isprogressively inflated by step of 5 mm Hg, from 0 to 75 mm Hg, each stepof inflation lasting 30 seconds. Each cycle of colonic distension iscontrolled by a standard barostat (ABS, St-Dié, France). The thresholdcorresponds to the pressure which produced the first abdominalcontraction and the cycle of distension is then discontinued. Thecolonic threshold (pressure expressed in mm Hg) is determined afterperformance of four cycles of distension on the same animal.

Determination of the Activity of the Compound

Data is analyzed by comparing test compound-treated group withTNBS-treated group and control group. Mean and sem are calculated foreach group. The antiallodynic activity of the compound is calculated asfollows:

Activity (%)=(group C−group T)/(group A−group T)

Group C: mean of the colonic threshold in the control group

Group T: mean of the colonic threshold in the TNBS-treated group

Group A: mean of the colonic threshold in the test compound-treatedgroup

Statistical Analysis

Statistical significance between each group was determined by using aone-way ANOVA followed by Student's unpaired t-test. Differences wereconsidered statistically significant at p<0.05.

Compounds

TNBS is dissolved in EtOH 30% and injected under a volume of 0.5 mL/rat.TNBS is purchased from Fluka.

Oral administration of the test compound or its vehicle is performed 1hour before the colonic distension cycle.

Sub-cutaneous administration of the test compound or its vehicle isperformed 30 minutes before the colonic distension cycle.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparations” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch formn the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the pharmaceutical methodof this invention are administered at the initial dosage of about 0.01mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

The following examples are illustrative of the synthetic procedures formaking the intermediates and final products of the instant invention.They are not intended to limit the scope of the invention.

EXAMPLE 1 (cis)-4-Isobutyl-pyrrolidine-3-carboxylic acid (see Scheme 3)

Step 1: Synthesis of 1,1-Dibromo-4-methyl-pent-1-ene

To a stirred solution of carbon tetrabromide (30 g, 90.63 mmol) indichloromethane (400 mL) at −10° C. was added triphenylphosphine (60 g,229 mmol) in portions. Internal temperature was kept below 5° C. duringthe addition, and it was stirred for additional 30 minutes at thistemperature after the addition was completed. Isovaleraldehyde 1 (9.4mL, 87.6 mmol) in methylene chloride (50 mL) was added slowly via asyringe, and the reaction was stirred for 3 hours during which thetemperature did not rise above 5° C. After the solvent was removed on arotary evaporator, pentane (600 mL) was added to the residue. The solidwhich separated was removed by filtration. Evaporation of solvent gave alight oil which was chromatographed on a silica gel column. The purecompound was eluted with pet ether to afford1,1-dibromo-4-methyl-pent-1-ene 6 (16.5g,78%).

NMR (CDCl₃): δ 6.38 (triplet, 1H), 1.95 (triplet, 2H), 1.70 (m, 1H), and0.89 (d, 6H).

Step 2: Synthesis of 5-Methyl-hex-2-ynoic acid ethyl ester

1,1-Dibromo-4-methyl-pent-1-ene 6 (40 g, 165.9 mmol) was dissolved indry THF (120 mL) and cooled to −78° C. While stirring, n-butyllithium(1.6 M solution in hexane, 190.8 mL, 305 mmol) was added dropwise in afew minutes. After 1 hour, ethyl chloroformate (15 mL, 154.5 mmol) wasadded, and the reaction was stirred overnight during which it warmed toroom temperature. It was poured onto water and extracted with ether(3×250 mL), dried on magnesium sulfate and evaporated. The light oil wasflash chromatographed on a silica gel column, and the compound waseluted with 10% ether in pet ether to afford 5-methyl-hex-2-ynoic acidethyl ester 7 (23.6 g, 92%).

NMR (CDCl₃): δ 4.14 (m, 2H), 2.16 (d, 2H), 1.85 (m, 1H), 1.24 (triplet,3H), and 0.94 (d, 6H).

Step 3: Synthesis of (Z)-5-Methyl-hex-2-enoic acid ethyl ester

5-Methyl-hex-2-ynoic acid ethyl ester 7 (20.97 g) in THF (540 mL),pyridine (60 mL), and 5% Pd/BaSO₄ (1.10 g) was hydrogenated in 3.25hours. The solvent was evaporated, and the light oil was chromatographedon a silica gel coulmn. After recovering some unreacted acetylene, theolefin was eluted with 5% ether in pet ether to give pure fractions of(Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (12.0 g).

NMR (CDCl₃): δ 6.22 (m, 1H), 5.74 (d, 1H), 4.10 (m, 2H), 2.51 (triplet,2H), 1.67 (m, 1H), 1.24 (triplet, 3H), and 1.16 (d, 6H).

N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (Reagent for Step 4)

n-Butyllithium (1.6 M solution in hexane, 34.85 mL, 55.76 mmol) wasadded to N-benzyltrimethylsilylmethylamine (10 g, 55.76 mmol) in dry THF(140 mL) and stirred at −78° C. under nitrogen atmosphere. After 45minutes, methoxymethyl chloride (4.3 mL, 55.76 mmol) in THF (6 mL) wasadded and then stirred for another 3 hours. The THF was evaporated, andthe residue was dissolved in hexane, washed with water, and dried oversodium sulfate. The solvent was evaporated to give under reducedpressure to give N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (10g).

Step 4: (cis)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethylester

N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (4.0 g, 16.8 mmol),followed by TFA (1.0 M solution in CH₂Cl₂, 1.0 mL, 1 mmol) were added toa solution of (Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (3.0 g, 19.2mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogenatmosphere. After 15 minutes, the bath was removed and stirring wascontinued overnight. The reaction mixture was washed with saturatedNaHCO₃ (10 mL), water (15 mL), brine (20 mL), and dried. The product waspurified by chromatography on silica gel, and compound was eluted with20% ethyl acetate in hexane to give(cis)-1-benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 9 asan oil (2.25 g, 41%).

Step 5: Synthesis of (cis)-4-Isobutyi-pyrrolidine-3-carboxylic acid

(cis)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 9(2.25 g, 7.78 mmol) in ethanol (75 mL) and 20% Pd/C (210 mg) washydrogenated for 5.5 hours. The reaction mixture was filtered through apad of Celite, and the filtrate was concentrated to give[3R-(cis)]-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 10 as anoil. Proton NMR showed the absence of a benzyl group. To the 10 wasadded 6N HCl (20 mL), and the solution was refluxed overnight. After thesolvent was evaporated at reduced pressure crude product was loaded ontoa column of Dowax 50WX8-100 ion-exchange resin (30 g) which had beenpre-washed to neutral (pH-7) with HPLC grade water. The resin was againwashed to pH-7, followed by elution of the compound with 0.5N ammoniumhydroxide solution. The solvent was evaporated, and the product wascrystallized from methanol-ether to give(cis)-4-isobutyl-pyrrolidine-3-carboxylic acid 11 (470 mg). Analysis bytlc (8% NH₄0H in 95% ethanol, visualized with ninhydrin) indicated thepresence of minor fast chromatographic spot (trans-isomer). The mixturewas adsorbed onto silica get and chromatographed on a Biotage Flashsystem. Compound was eluted with 5% NH₄OH in 95% ethanol. Afterevaporation of solvent, the product was converted to the HCl salt andreprocessed on ion-exchange column, followed by crystalization frommethanol-ether to give (cis)-4-isobutyl-pyrrolidine-3-carboxylic acid 11(320 mg).

¹H NMR (400 MHz, CD₃OD): δ 3.46 (dd, 1H), 3.31 (dd, 1H), 3.18 (dd, 1H),3.15 (m, 1H), 2.49 (m, 1H), 1.63 (m, 1H), 1.47 (m, 1H), 1.25 (m, 1H),and 0.88 (6H). Anal. Calcd for C₉H₁₇NO₂: C, 63.13; H, 10.01; N, 8.18.Found: C, 62.86; H, 9.82; N, 8.05.

EXAMPLE 2 [trans]-4-Isobutyl-pyrrolidine-3-carboxylic acid (See Scheme4)

Step 1: (E)-5-Methyl-hex-2-enoic acid ester

Sodium hydride (60% dispersion in oil) (3.87 g, 96.7 mmol) was washedwith pentane and stirred in dimethoxyethane (80 mL). While cooling inice bath, a solution of triethyl phosphonoacetate (21.7 g, 96.7 mmol)was added slowly in 15 minutes. The reaction was stirred for additional15 minutes and isovaleraldehyde 1 (31 mL, 290 mmol) in dimethoxyethane(20 mL) was added in one portion. It was refluxed overnight,concentrated, and hexane/water (500 mL, 3/2v/v) was added. The organicportion was separated, washed with water (200 mL), brine (2×200 mL) anddried on magnesium sulfate. Evaporation of solvent gave an oil which waspurified by flash chromatography on silica gel. The compound was elutedwith 30% methylene chloride in pet ether to give(E)-5-methyl-hex-2-enoic acid ester 2 as a clear liquid (13.2 g).

NMR (CDCl₃): δ 6.89 (m, 1H), 5.75 (d, 1H), 4.14 (m, 2H), 2.05 (m, 2H),1.69 (m, 1H), 1.25 (triplet, 3H), and 0.88 (d, 6H).

Step 2: Synthesis of[trans]-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester

N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (2.84 g, 12 mmol),followed by TFA (1.0 M solution in CH₂Cl₂, 1.0 mL, 1 mmol) were added toa solution of (E)-5-methyl-hex-2-enoic acid ethyl ester (1.56 g, 10.0mmol) in methylene chloride (30 mL) maintained at −5° C. under nitrogenatmosphere. After 15 minutes, the bath was removed and stirring wascontinued overnight. Saturated sodium bicarbonate was added, and theorganic portion was separated, washed with brine, and dried. The productwas purified by chromatography on silica gel, and compound was elutedwith 20% ethyl acetate in hexane to give(trans)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 3as an oil (1.28 g, 44%).

NMR (CDCl₃): δ 7.28 (m, 5H), 4.09 (m, 2H), 3.56 (q, 2H), 2.81 (m, 2H),2.69 (triplet, 1H), 2.51 (m, 2H), 2.18 (triplet, 1H), 1.51 (m, 1H), 1.38(m, 1H), 1.27 (m, 1H), 1.20 (triplet, 3H), and 0.83 (d, 6H).

Step 3: [trans]-4-Isobutyl-pyrrolidine-3-carboxylic acid

(trans)-1-Benzyl-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 3(1.28 g, 4.42 mmol) in ethanol (75 mL) and 20% Pd/C (210 mg) washydrogenated for 5.5 hours. The reaction mixture was filtered through apad of Celite, and the filtrate was concentrated to give[3R-(trans)]-4-isobutyl-pyrrolidine-3-carboxylic acid ethyl ester 4 asan oil. Proton NMR (CDCl₃): δ 4.13 (m, 2H), 3.18 (m, 1H), 3.15 (m, 1H),3.08 (m, 1H), 2.67 (brs, 1H), 2.46 (m, 2H), 2.34 (m, 1H), 1.55 (m, 1H),1.37 (m, 1H), 1.25 (triplet, 3H) and 0.87 (q, 6H) showed the absence ofa benzyl group. To the residue was added 6N HCl (20 mL), and thesolution was refluxed overnight. After the solvent was evaporated atreduced pressure, crude product was loaded onto a column of Dowax50WX8-100 ion-exchange resin (28 g) which had been pre-washed to neutral(pH-7) with hplc grade water. The resin was again washed to pH-7,followed by elution of the compound with 0.5N ammonium hydroxidesolution. The fractions were monitored by tic (8% NH₄OH in 95% ethanol,visualized with ninhydrin). The solvent was evaporated and the compoundcrystallized from methanol-ether to give(trans)-4-isobutyl-pyrrolidine-3-carboxylic acid 5 (280 mg). ¹H NMR (400MHz, CD₃OD): δ 3.44 (dd, 1H), 3.37 (d, 2H), 2.78 (dd, 1H), 2.52 (m, 2H),1.60 (m, 1H), 1.51 (m, 1H), 1.26 (m, 1H), 0.89 (6H).

Anal. Calcd. for C₉H₁₇NO₂: C, 63.13; H, 10.01; N, 8.18. Found: C, 62.79;H, 9.45; N, 8.02.

General Procedure for the Preparation of1-Benzyl-4-alkylpyrrolidine-3-carboxylic acid ethyl ester 2a-2h

To a stirred solution of α,β-unsaturated carboxylic acid ethyl ester1a-1h (11.70 mmol) in toluene (20 mL) was addedN-benzyl-N-(methoxymethyl) trimethylsilylmethylamine (3.33 g, 14.10mmol) at 0° C. under N₂. After 20 minutes, a solution of TFA (1 M inCH₂Cl₂, 1.17 mmol) was added slowly at 0° C. The mixture was stirred at0° C. for 30 minutes and then at 22° C. for an additional 12 hours. Thereaction was quenched with H₂O, extracted with CHCl₃, then dried overMgSO₄. The solvent was evaporated to dryness, and the oily residue wassubjected to column chromatography (silica gel, hexanes:ether=6:1) togive 2a-2h as a colorless oil.

trans-1-Benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester (2a).yield 100%; ¹H NMR (CDCl₃): δ 1.07 (d, J=6.6 Hz, 3 H, CH₃), 1.18 (t,J=7.1 Hz, 3 H, CH₂CH ₃), 2.13-2.17 (m, 1 H, pyrrolidine ring), 2.40-2.50(m, 2 H, pyrrolidine ring), 2.68-2.82 (m, 3 H, pyrrolidine ring),3.48-3.59 (ABq, J=32.9 Hz, 2 H, CH₂Ph), 4.04-4.09 (q, J=7.1 Hz, 2 H, CH₂CH₃), 7.17-7.25 (m, 5 H, aromatic ring); ¹³C(CDCl₃): δ 14.24, 19.74,36.78, 50.65, 56.64, 60.09, 60.44, 61.63, 126.87, 128.19, 128.66,138.98,174.67; MS (CI) m/z 248 (M+1)⁺. Anal. (C₁₅H₂₁NO₂) C, H, N.

1-Benzyl-4,4-dimethylpyrrolidine-3-carboxylic acid ethyl ester (2b).yield 28%; ¹H NMR (CDCl₃): δ 0.93 (s, 3 H, CH₃), 1.17 (s, 3 H, CH₃),1.17-1.21 (t, J=7.0 Hz, 3 H, CH₂CH ₃), 2.20-2.87 (m, 5 H, pyrrolidinering), 3.50-3.59 (ABq, J=26.2 Hz, 2 H, CH₂Ph), 4.03-4.14 (m, 2 H, CH₂CH₃), 7.13-7.30 (m, 5 H, aromatic ring); ¹³C(CDCl₃): δ 14.41, 24.15,29.59, 41.49, 53.45, 55.84, 60.14, 60.18, 68.14, 126.82, 128.20, 128.55,139.41, 173.33; MS (CI) m/z 262 (M+1)⁺. Anal. (C₁₆H₂₃NO₂) C, H, N.

trans-1-Benzyl-4-ethylpyrrolidine-3-carboxylic acid ethyl ester (2c).yield 95%; ¹H NMR (CDCl₃): δ 0.86 (t, J=7.3 Hz, 3 H, CH₂CH ₃), 1.21 (t,J=7.1 Hz, 3 H, OCH₂CH ₃), 1.37-1.57 (m, 2 H, CH ₂CH₃), 2.22-2.79 (m, 5H, pyrrolidine ring), 3.51-3.64 (ABq, J=39.3 Hz, 2 H, CH₂Ph), 4.08-4.13(m, 2 H, OCH ₂CH₃), 7.23-7.29 (m, 5 H, aromatic ring); ¹³C(CDCl₃): δ12.46, 14.25, 28.05, 43.73, 48.97, 56.84, 59.72, 60.07, 60.49, 126.89,128.21, 128.64, 139.02, 175.01; MS (CI) m/z 262 (M+1)⁺. Anal.(C₁₆H₂₃NO₂) C, H, N.

trans-1-Benzyl-4-isopropylpyrrolidine-3-carboxylic acid ethyl ester(2d). yield 79%; ¹H NMR (CDCl₃): δ 0.84-0.88 (m, 6 H, CH₃, CH₃),1.20-1.22 (t, J=8.0 Hz, 3 H, CH₂CH ₃), 1.54-1.62 (m, 1 H, CH(CH₃)₂),2.24-2.32 (m, 2 H, pyrrolidine ring), 2.63-2.69 (m, 2 H, pyrrolidinering), 2.74-2.80 (m, 2 H, pyrrolidine ring), 3.47-3.65 (ABq, J=56.4 Hz,2 H, CH₂Ph), 4.06-4.14 (m, 2 H, CH ₂CH₃), 7.19-7.30 (m, 5 H, aromaticring); ¹³C(CDCl₃): δ 14.19, 20.59, 20.81, 32.20, 47.16, 48.67, 57.56,58.23, 59.99, 60.45, 126.82, 128.17, 128.54, 139.05, 175.33; MS (CI) m/z276 (M+1)⁺. Anal. (C₁₇H₂₅NO₂) C, H, N.

trans-1-Benzyl-4-propylpyrrolidine-3-carboxylic acid ethyl ester (2e).yield 72%; ¹H NMR (CDCl₃): δ 0.84-0.88 (t, J=7.1 Hz, 3 H, CH₂CH₂CH ₃),1.20-1.24 (t, J=7.1 Hz, 3 H, CH₂CH ₃), 1.26-1.54 (m, 4 H, CH ₂CH ₂CH₃),2.21-2.82 (m, 6 H, pyrrolidine ring), 3.51-3.64 (ABq, J=40.6 Hz, 2 H,CH₂Ph), 4.07-4.16 (m, 2 H, CH ₂CH₃), 7.19-7.31 (m, 5 H, aromatic ring);¹³C(CDCl₃): δ 14.09, 14.22, 21.13, 37.51, 41.74, 49.25, 56.75, 59.98,60.05, 60.43, 126.84, 128.18, 128.61, 139.01, 174.95; MS (CI) m/z 276(M+1)⁺. Anal. (C₁₇H₂₅NO₂) C, H, N.

trans-1-Benzyl-4-isobutylpyrrolidine-3-carboxylic acid ethyl ester (2f).yield 99%; ¹H NMR (CDCl₃): δ 0.83-0.88 (d, J=7.1 Hz, 6 H, CH(CH ₃)₂),1.20-1.24 (t, J=7.1 Hz, 3 H, CH₂CH ₃), 1.27-1.51(m, 3 H, CH ₂CH(CH₃)₂),2.18-2.81 (m, 6 H, pyrrolidine ring), 3.50-3.65 (ABq, J=43.4 Hz, 2 H,CH₂Ph), 4.07-4.15 (m, 2 H, CH ₂CH₃), 7.21-7.30 (m, 5 H, aromatic ring);¹³C(CDCl₃): δ 14.22, 22.42, 22.92, 26.46, 39.89, 44.84, 49.48, 56.65,60.07, 60.33, 60.44, 126.87, 128.19, 128.63, 138.95, 174.93; MS (CI) m/z290 (M+1)⁺. Anal. (C₁₈H₂₇NO₂) C, H, N.

trans-1-Benzyl-4-butylpyrrolidine-3-carboxylic acid ethyl ester (2f).yield 82%; ¹H NMR (CDCl₃): δ 0.85 (t, J=7.1 Hz, 3 H, CH₂CH₂CH ₃),1.20-1.24 (t, J=7.1 Hz, 3 H, CH₂CH ₃), 1.27-1.51 (m, 3 H, CH ₂CH(CH₃)₂),2.18-2.81 (m, 6 H, pyrrolidine ring), 3.50-3.65 (ABq, J=43.4 Hz, 2 H,CH₂Ph), 4.07-4.15 (m, 2 H, CH ₂CH₃), 7.20-7.30 (m, 5 H, aromatic ring);¹³C(CDCl₃): δ 13.98, 14.22, 19.18, 22.67, 30.19, 34.93, 41.95, 49.27,56.75, 60.06, 60.44, 126.84, 128.18, 128.62, 139.00, 174.95; MS (CI) m/z290 (M+1)⁺. Anal. (C₁₈H₂₇NO₂) C, H, N.

General Procedure for the Preparation of 4-Alkylpyrrolidine-3-carboxylicacid 3a-3h. (Scheme 5)

To a solution of 1-benzyl-4-alkylpyrrolidine-3-carboxylic acid ethylester 2a-2h (4.42 mmol) in ethanol (75 mL) was added 20% Pd/C (0.21 g)and hydrogenated at 50 psi for 11 hours. The reaction mixture wasfiltered through a pad of celite. The filtrate was concentrated to give4-alkylpyrrolidine-3-carboxylic acid ethyl ester as an oil. To the crudeoil was added 3N HCl (20 mL). The reaction mixture was refluxed for 12hours. After the solvent was evaporated at reduced pressure, the crudeproduct was subjected to ion exchange column (Dowex 50) andrecrystallized from methanol-ether to give4-alkylpyrrolidine-3-carboxylic acid 3a-3h as a white solid.

trans-4-Methylpyrrolidine-3-carboxylic acid (3a). yield 90%; mp 208-210°C.; ¹H NMR (CD₃OD): δ 1.14 (d, J=6.3 Hz, 3 H, CH₃), 2.42-2.54 (m, 2 H,pyrrolidine ring), 2.74-2.79 (m, 1 H, pyrrolidine ring), 3.71-3.46 (m, 3H, pyrrolidine ring); ¹³C(CD₃OD): δ 15.77, 37.72, 48.33, 51.34, 52.75,177.16; MS (CI) m/z 130 (M+1)⁺. Anal. (C₆H₁₁NO₂) C, H, N.

trans-4,4-Dimethylpyrrolidine-3-carboxylic acid (3b). yield 84%; mp282-286° C.; ¹H NMR (CD₃OD): δ 1.11 (s, 3 H, CH₃), 1.21 (s, 3 H, CH₃),2.59-2.63 (m, 1 H, pyrrolidine ring), 2.94 (d, J=11.3 Hz, 1 H,pyrrolidine ring), 3.15 (d, J=11.3 Hz, 1 H, pyrrolidine ring), 3.36-3.41(m, 1 H, pyrrolidine ring), 3.53-3.58 (m, 1 H, pyrrolidine ring);¹³C(CD₃OD): δ 21.33, 25.87, 41.05, 48.21, 55.51, 56.50, 177.10; MS (CI)m/z 144 (M+1)⁺. Anal. (C₇H₁₃NO₂) C, H, N.

trans-4-Ethylpyrrolidine-3-carboxylic acid (3c). yield 78%; mp 197-199°C.; ¹H NMR (CD₃OD): δ 0.98 (m, 3 H, CH₃), 1.41-1.44 (m, 1 H, CH ₂CH₃),1.65-1.70 (m, 1 H, CH ₂CH₃), 2.34-2.39 (m, 1 H, pyrrolidine ring),2.56-2.62 (m, 1 H, pyrrolidine ring), 2.80-2.88 (m, 1 H, pyrrolidinering), 3.36-3.48 (m, 3 H, pyrrolidine ring); ¹³C(CD₃OD): δ 11.10, 25.35,44.47, 48.46, 49.65, 51.07, 177.60; MS (CI) m/z 144 (M+1)⁺. Anal.(C₇H₁₃NO₂) C, H, N.

trans-4-Isopropylpyrrolidine-3-carboxylic acid (3d). yield 88%; mp243-245° C.; ¹H NMR (CD₃OD): δ 0.92 (d, J=6.5 Hz, 3 H, CH₃), 0.99 (d,J=6.5 Hz, 3 H, CH₃), 1.67-1.72 (m, 1 H, CH(CH₃)₂), 2.29-2.37 (m, 1 H,pyrrolidine ring), 2.66-2.72 (m, 1 H, pyrrolidine ring), 2.89-2.94 (m, 1H, pyrrolidine ring), 3.31-3.45 (m, 3 H, pyrrolidine ring); ¹³C(CD₃OD):δ 19.00, 19.94, 30.32, 48.22, 49.20,49.26, 49.40, 178.18; MS (CI) m/z158 (M+1)⁺. Anal. (C₈H₁₅NO₂) C, H, N.

trans-4-Propylpyrrolidine-3-carboxylic acid (3e). yield 88%; mp 223-226°C.; ¹H NMR (CD₃OD): δ 0.92 (t, J 6.6 Hz, 3 H, CH₃), 1.32-1.40 (m, 3 H,CH ₂CH ₂), 1.61 (m, 1 H, CH ₂CH₂), 2.42-2.46 (m, 1 H, pyrrolidine ring),2.55-2.60 (q, J=7.5 Hz, 1 H, pyrrolidine ring), 2.80-2.85 (t, J=11.3 Hz,1 H, pyrrolidine ring), 3.38-3.47 (m, 3 H, pyrrolidine ring);¹³C(CD₃OD): δ 12.96, 20.69, 34.68, 42.62, 48.45, 49.94, 51.43, 177.51;MS (CI) m/z 158 (M+1)⁺. Anal. (C₈H₁₅NO₂) C, H, N.

trans-4-Isobutylpyrrolidine-3-carboxylic acid (3f). yield 86%; mp255-257° C.; ¹H NMR (CD₃OD): δ 0.89 (m, 6 H, CH₃), 1.26 (m, 1 H,CH₂CH(CH₃)₂), 1.51 (m, 1 H, CH ₂CH(CH₃)₂), 1.60 (m, 1 H, CH ₂CH(CH₃)₂),2.52 (m, 2 H, pyrrolidine ring), 2.78 (m, 1 H, pyrrolidine ring), 3.37(m, 2 H, pyrrolidine ring), 3.44 (m, 1 H, pyrrolidine ring); ¹³C(CD₃OD):δ 21.07, 22.07, 26.29, 40.81, 41.83, 48.39, 50.11, 51.78, 177.47; MS(CI) m/z 172 (M+1)⁺. Anal. (C₉H₁₇NO₂) C,H,N.

cis-4-Isobutylpyrrolidine-3-carboxylic acid (3g). yield 85%; mp 260-262°C.; ¹H NMR (CD₃OD): δ 0.88 (m, 6 H, CH₃), 1.25 (m, 1 H, CH₂CH(CH₃)₂),1.47 (m, 1 H, CH ₂CH(CH₃)₂), 1.63 (m, 1 H, CH ₂CH(CH₃)₂), 2.49 (m, 1 H,pyrrolidine ring), 3.15 (m, 1 H, pyrrolidine ring), 3.18 (m, 1 H,pyrrolidine ring), 3.31-3.46 (m, 3 H, pyrrolidine ring; MS (CI) m/z 172(M+1)⁺. Anal. (C₉H₁₇NO₂) C, H, N.

trans-4-Butylpyrrolidine-3-carboxylic acid (3h). yield 85%; mp 234-237°C.; ¹H NMR (CD₃OD): δ 0.89 (m, 3 H, CH₃), 1.33 (m, 5 H, CH ₂CH ₂CH ₂),1.65 (m, 1 H, CH ₂CH₂CH₂), 2.38-2.43 (m, 1 H, pyrrolidine ring),2.55-2.60 (q, J=7.5 Hz, 1 H, pyrrolidine ring), 2.80-2.85 (t, J=8.8 Hz,1 H, pyrrolidine ring), 3.28-3.48 (m, 3 H, pyrrolidine ring);¹³C(CD₃OD): δ 12.85, 22.33, 29.77, 32.20, 42.83, 48.39, 49.91, 51.43,177.62; MS (CI) m/z 172 (M+1)⁺. Anal. (C₉H₁₇NO₂) C, H, N.

3-[(E)-3-Isobutylpropenoyl]-4-(S)-phenyl-2-oxazolidinone (7a). (Scheme6)

To a solution of (E)-5-methyl-hex-2-enoic acid (3.2 g, 25 mmol) intoluene (20 mL) was added oxalyl chloride (4.4 mL, 50 mmol) slowly at 0°C. under N₂ followed by one drop of DMF. The mixture was stirred at 22°C. for 1 hour. The volatiles were removed under reduced pressure to givethe desired acid chloride which was used without further purification.To a solution of NaH (0.84 g, 21 mmol) in THF (30 mL) was added asolution of (S)-(−)-4-phenyl-2-oxazolidinone (3.4 g, 21 mmol) in THF (10mL) at 0° C. The mixture was stirred at 22° C. for 1 hour. The crudeacid chloride was then introduced while maintaining the temperature at0° C. The mixture was stirred at 0° C. for 1 hour and then at 22° C. foran additional 12 hours. The reaction was quenched with 1N HC1 aqueoussolution, extracted with CHCl₃, then dried over Na₂SO₄. After thesolvent was evaporated at reduced pressure, the crude product wassubjected to column chromatography (silica gel, hexanes:ether=2:1) togive 6.25 g (100% yield) of 7a as a white solid. mp 84-85° C.; ¹H NMR(CDCl₃): δ 0.81 (d, J=6.8 Hz, 6 H, CH(CH ₃)₂), 1.68-1.78 (m, 1 H,CH₂CH(CH₃)₂), 2.11-2.14 (m, 2 H, CH ₂CH(CH₃)₂), 4.24-4.27 (m, 1 H,oxazolidinone ring), 4.65-4.72 (t, J=8.8 Hz, 1 H, oxazolidinone ring),5.44-5.48 (m, 1 H, oxazolidinone ring), 7.02-7.09 (m, 1 H, vinyl),7.23-7.28 (m, 1 H, vinyl), 7.31-7.38 (m, 5 H, aromatic); ¹³C(CDCl₃): δ22.35, 22.39, 27.88, 41.82, 57.77, 69.92, 121.11, 125.95, 128.63,129.16, 139.14, 151.10, 153.70, 164.56; MS (CI) m/z 274 (M+1)⁺. Anal.(C₁₆H₁₉NO₃) C, H, N.

1-Benzyl-4-(R)-isobutyl-3-(R)-[4′-(S)-phenyl-2′-oxazolidinon-3′-yl]carbonyl]pyrrolidine(8a). (Scheme 6)

To a stirred solution of3-[(E)-3-isobutylpropenoyl]-4-(S)-phenyl-2-oxazolidinone (1.50 g, 5.50mmol) in toluene (20 mL) was added N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (1.56 g, 6.60 mmol) at 0° C. under N₂. After20 minutes, a solution of TEA (1 M in CH₂Cl₂, 0.55 mmol) was addedslowly at 0C. The mixture was stirred at 0° C. for 30 minutes and thenat 22° C. for an additional 12 hours. The reaction was quenched withH₂O, extracted with CHCl₃, then dried over MgSO₄. The solvent wasevaporated to dryness, and the oily residue was subjected to columnchromatography (silica gel, hexanes:ether2:1) to give 1.37 g (62% yield)of 8a as a white solid. ¹H NMR (CDCl₃): δ 0.84-0.86 (m, 6 H, CH(CH ₃)₂),1.26-1.29 (m, 2 H, CH ₂CH(CH₃)₂), 1.42-1.47 (m, 1 H, CH₂CH(CH₃)₂), 2.08(t, J=7.3 Hz, 1 H, pyrrolidine ring), 2.62 (dd, J=9.8 Hz, 4.6 Hz, 1 H,pyrrolidine ring), 2.83-2.94 (m, 3 H, pyrrolidine ring), 3.37-3.67 (ABq,2 H, CH₂Ph), 3.68-3.72 (m, 1 H, pyrrolidine ring), 4.16-4.19 (m, 1 H,oxazolidinone ring), 4.63 (t, J=9.0 Hz, 1 H, oxazolidinone ring), 5.40(m, 1 H, oxazolidinone ring), 7.18-7.36 (m, 5 H, aromatic); ¹³C(CDCl₃):δ 22.46, 23.05, 26.72, 37.00, 44.07, 49.41, 57.48, 57.85, 59.84, 60.54,69.87, 125.67, 126.80, 128.21, 128.48, 128.65, 129.25, 139.01, 139.05,153.55, 173.71; MS (CI) m/z 407 (M+1)⁺. Anal. (C₂₅H₃₀N₂O₃) C, H, N.

trans-4-(R)-Isobutylpyrrolidine-3-(R)-carboxylic acid (10a). (Scheme 6)

To a solution of1-benzyl-4-(R)-isobutyl-3-(R)-[4′-(S)-phenyl-2′-oxazolidinon-3′-yl)carbonyl]pyrrolidine(1.37g, 3.37 mmol) in THF (30 mL)was added a solution of LiOH (1 M inH₂O, 8.44 mmol) and H₂O₂ (30%, 6.75 mmol) in H₂O (10 mL) at 0° C.slowly. The reaction mixture was stirred at 0° C. for 1 hour, thendiluted with water (40 mL). Sodium sulfite (0.85 g, 6.75 mmol) wasadded, and the mixture was extracted with ethyl acetate. The aqueousphase was adjusted to pH 5.0 with KH₂PO₄ (1.51 g, 11.1 mmol) and 10%HCl. This solution was extracted with isopropyl alcohol:methylenechloride (1:3), which was dried over Na₂SO₄ and concentrated to afford0.88 g of 1-benzyl-4-(R)-isobutylpyrrolidine-3-(R)-carboxylic acid whichwas used without further purification. To a solution of this carboxylicacid (0.72 g) in ethanol (55 mL) was added 20% Pd/C (0.11 g) andhydrogenated at 50 psi for 11 hours. The reaction mixture was filteredthrough a pad of celite. After the solvent was evaporated at reducedpressure, the crude product was subjected to ion exchange column (Dowex50) and recrystallized from methanol-ether to give 0.33 g (71% yield) of10a as a white solid. [α]_(D)=+44.8°; mp 236-239° C.; ¹H NMR (CD₃OD): δ0.89 (m, 6 H, CH₃), 1.26 (m, 1 H, CH₂CH(CH₃)₂), 1.51 (m, 1 H, CH₂CH(CH₃)₂), 1.60 (m, 1 H, CH ₂CH(CH₃)₂), 2.52 (m, 2 H, pyrrolidinering), 2.78 (m, 1 H, pyrrolidine ring), 3.37 (m, 2 H, pyrrolidine ring),3.44 (m, 1 H, pyrrolidine ring); ¹³C(CD₃OD): δ 21.07, 22.07, 26.29,40.81, 41.83, 48.39, 50.11, 51.78, 177.47; MS (CI) m/z 172 (M+1)⁺. Anal.(C₉H₁₇NO₂) C, H, N.

3-[(E)-3-Isobutylpropenoyl]-4-(R)-phenyl-2-oxazolidinone (7b). (Scheme6)

To a solution of (E)-5-methyl-hex-2-enoic acid (1.77 g, 13.8 mmol) intoluene (20 mL) was added oxalyl chloride (2.4 mL, 27.6 mmol) slowly at0° C. under N₂ followed by one drop of DMF. The mixture was stirred at22° C. for 1 hour. The volatiles were removed under reduced pressure togive the desired acid chloride which was used without furtherpurification. To a solution of NaH (0.37 g, 9.2 mmol) in THF (30 mL) wasadded a solution of (R)-(−)-4-phenyl-2-oxazolidinone (1.5 g, 9.2 nmmol)in THF (10 mL) at 0° C. The mixture was stirred at 22° C. for 1 hour.The crude acid chloride was then introduced while maintaining thetemperature at 0° C. The mixture was stirred at 0° C. for 1 hour andthen at 22° C. for an additional 12 hours. The reaction was quenchedwith 1N HCl aqueous solution, extracted with CHCl₃, then dried overNa₂SO₄. After the solvent was evaporated at reduced pressure, the crudeproduct was subjected to column chromatography (silica gel,hexanes:acetone=3:1) to give 2.5 g (100% yield) of 7b as a white solid.mp 84-85° C.; ¹H NMR (CDCl₃): δ 0.81 (d, J=6.8 Hz, 6 H, CH(CH ₃)₂),1.68-1.78 (mn, 1 H, CH₂CH(CH₃)₂), 2.11-2.14 (m, 2 H, CH ₂CH(CH₃)₂),4.24-4.27 (m, 1 H, oxazolidinone ring), 4.65-4.72 (t, J=8.8 Hz, 1 H,oxazolidinone ring), 5.44-5.48 (m, 1 H, oxazolidinone ring), 7.02-7.09(m, 1 H, vinyl), 7.23-7.28 (m, 1 H, vinyl), 7.31-7.38 (m, 5 H,aromatic); ¹³C(CDCl₃): δ 22.35, 22.39, 27.88, 41.82, 57.77, 69.92,121.11, 125.95, 128.63, 129.16, 139.14, 151.10, 153.70, 164.56; MS (CI)m/z 274 (M+1)⁺. Anal. (C₁₆H₁₉NO₃) C,H, N.

1-Benzyl-4-(S)-isobutyl-3-(S)-[4′-(R)-phenyl-2′-oxazolidinon-3′-yl]carbonyl]pyrrolidine(8b).

To a stirred solution of3-[(E)-3-isobutylpropenoyl]-4-(R)-phenyl-2-oxazolidinone (1.50 g, 5.50mmol) in toluene (20 mL) was added N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (1.56 g, 6.60 mmol) at 0° C. under N₂. After20 minutes, a solution of TFA (1 M in CH₂Cl₂, 0.55 mmol) was addedslowly at 0° C. The mixture was stirred at 0° C. for 30 minutes and thenat 22° C. for an additional 12 hours. The reaction was quenched withH₂O, extracted with CHCl₃, then dried over MgSO₄. The solvent wasevaporated to dryness, and the oily residue was subjected to columnchromatography (silica gel, hexanes:ether=2:1) to give 1.45 g (65%yield) of 8b as a white solid. ¹H NMR (CDCl₃): δ 0.84-0.86 (m, 6 H,CH(CH ₃)₂), 1.26-1.29 (m, 2 H, CH ₂CH(CH₃)₂), 1.42-1.47 (m, 1 H,CH₂CH(CH₃)₂), 2.08 (t, J=7.3 Hz, 1 H, pyrrolidine ring), 2.62 (dd, J=9.8Hz, 4.6 Hz, 1 H, pyrrolidine ring), 2.83-2.94 (m, 3 H, pyrrolidinering), 3.37-3.67 (ABq, 2 H, CH₂Ph), 3.68-3.72 (m, 1 H, pyrrolidinering), 4.16-4.19 (m, 1 H, oxazolidinone ring), 4.63 (t, J=9.0 Hz, 1 H,oxazolidinone ring), 5.40 (m, 1 H, oxazolidinone ring), 7.18-7.36 (m, 5H, aromatic); ¹³C(CDCl₃): δ 22.46, 23.05, 26.72, 37.00, 44.07, 49.41,57.48, 57.85, 59.84, 60.54, 69.87, 125.67, 126.80, 128.21, 128.48,128.65, 129.25, 139.01, 139.05, 153.55, 173.71; MS (CI) m/z 407 (M+1)⁺.Anal. (C₂₅H₃₀N₂O₃) C, H, N.

trans-4-(S)-Isobutylpyrrolidine-3-(S)-carboxylic acid (10b). (Scheme 6)

To a solution of1-benzyl-4-(S)-isobutyl-3-(S)-[4′-(R)-phenyl-2′-oxazolidinon-3′-yl)carbonyl]pyrrolidine(1.44 g, 3.56 mmol) in THF (30 mL)was added a solution of LiOH (1 M inH₂O, 8.89 mmol) and H₂O₂ (30%, 7.11 mmol) in H₂O(10 mL) at 0° C. slowly.The reaction mixture was stirred at 0° C. for 1 hour, then diluted withwater (40 mL). Sodium sulfite (0.89 g, 7.11 mmol) was added, and themixture was extracted with ethyl acetate. The aqueous phase was adjustedto pH 5.0 with KH₂PO₄ (1.59 g, 11.7 mmol) and 10% HCl. This solution wasextracted with isopropyl alcohol:methylene chloride (1:3), which wasdried over Na₂SO₄ and concentrated to afford 0.93 g of1-benzyl-4-(S)-isobutylpyrrolidine-3-(S)-carboxylic acid which was usedwithout further purification. To a solution of this carboxylic acid(0.94 g) in ethanol (55 mL) was added 20% Pd/C (0.21 g) and hydrogenatedat 50 psi for 11 hours. The reaction mixture was filtered through a padof celite. After the solvent was evaporated at reduced pressure, thecrude product was subjected to ion exchange column (Dowex 50) andrecrystallized from methanol-ether to give 0.43 g (70% yield) of 10b asa white solid. [α]_(D)=−45.8°; mp 251-254° C.; ¹H NMR (CD₃OD): δ 0.89(m, 6 H, CH₃), 1.26 (m, 1 H, CH₂CH(CH₃)₂), 1.51 (m, 1 H, CH ₂CH(CH₃)₂),1.60 (m, 1 H, CH ₂CH(CH₃)₂), 2.52 (m, 2 H, pyrrolidine ring), 2.78 (m, 1H, pyrrolidine ring), 3.37 (m, 2 H, pyrrolidine ring), 3.44 (m, 1 H,pyrrolidine ring); ¹³C(CD₃OD): δ 21.07, 22.07, 26.29, 40.81, 41.83,48.39, 50.11, 51.78, 177.47; MS (CI) m/z 172 (M+1)⁺. Anal. (C₉H₁₇NO₂) C,H, N.

What is claimed is:
 1. A compound of formula I

or a pharmaceutically acceptable salt thereof or a prodrug thereofwherein R₁ is hydrogen or a straight or branched alkyl of from 1 to 5carbons; R₂ is a straight or branched alkyl of from 1 to 5 carbons; andR₁ and R₂ when taken together form a carbocyclic ring of from 3 to 7atoms.
 2. A compound according to claim 1 wherein R₁ is H, methyl, orethyl; and R₂ is methyl or ethyl.
 3. A compound according to claim 1 andselected from (cis)-4-isobutyl-pyrrolidine-3-carboxylic acid and(trans)-4-isobutyl-pyrrolidine-3-carboxylic acid.
 4. A compoundaccording to claim 1 wherein R₁ and R₂ are taken to form a carbocylicring of from 3 to 7 atoms.
 5. A compound according to claim 1 andselected from where R₁ and R₂ form a five or six membered ring.
 6. Acompound of Formula I

or a pharmaceutically acceptable salt thereof wherein R₄ is a alkyl of 3or 4 carbons.
 7. A compound according to claim 6 and selected from:trans-4-isopropylpyrrolidine-3-carboxylic acid;trans-4-propyl-pyrrolidine-3-carboxylic acid; andtrans-4-butyl-pyrrolidine-3-carboxylic acid.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 9. Amethod for treating epilepsy comprising administering a therapeuticallyeffective amount of a compound according to claim 1 to a mammal in needof said treatment.
 10. A method for treating faintness attacks,hypokinesia, and cranial disorders comprising administering atherapeutically effective amount of a compound according to claim 1 to amammal in need of said treatment.
 11. A method for treatingneurodegenerative disorders comprising administering a therapeuticallyeffective amount of a compound according to claim 1 to a mammal in needof said treatment.
 12. A method for treating depression comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a mammal in need of said treatment.
 13. A method fortreating anxiety comprising administering a therapeutically effectiveamount of a compound according to claim 1 to a mammal in need of saidtreatment.
 14. A method for treating panic comprising administering atherapeutically effective amount of a compound according to claim 1 to amammal in need of said treatment.
 15. A method for treating paincomprising administering a therapeutically effective amount of acompound according to claim 1 to a mammal in need of said treatment. 16.A method for treating neuropathological disorders comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a mammal in need of said treatment.